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Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa
Synaptic loss, neuronal death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa (RP), the leading cause of inherited blindness, is a group of retinal dystrophies characterized by photoreceptor dysfunction and death. The insulin re...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021205/ https://www.ncbi.nlm.nih.gov/pubmed/35444190 http://dx.doi.org/10.1038/s41419-022-04839-0 |
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author | Sánchez-Cruz, Alonso Hernández-Pinto, Alberto Lillo, Concepción Isiegas, Carolina Marchena, Miguel Lizasoain, Ignacio Bosch, Fátima de la Villa, Pedro Hernández-Sánchez, Catalina de la Rosa, Enrique J. |
author_facet | Sánchez-Cruz, Alonso Hernández-Pinto, Alberto Lillo, Concepción Isiegas, Carolina Marchena, Miguel Lizasoain, Ignacio Bosch, Fátima de la Villa, Pedro Hernández-Sánchez, Catalina de la Rosa, Enrique J. |
author_sort | Sánchez-Cruz, Alonso |
collection | PubMed |
description | Synaptic loss, neuronal death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa (RP), the leading cause of inherited blindness, is a group of retinal dystrophies characterized by photoreceptor dysfunction and death. The insulin receptor, a key controller of metabolism, also regulates neuronal survival and synaptic formation, maintenance, and activity. Indeed, deficient insulin receptor signaling has been implicated in several brain neurodegenerative pathologies. We present evidence linking impaired insulin receptor signaling with RP. We describe a selective decrease in the levels of the insulin receptor and its downstream effector phospho-S6 in retinal horizontal cell terminals in the rd10 mouse model of RP, as well as aberrant synapses between rod photoreceptors and the postsynaptic terminals of horizontal and bipolar cells. A gene therapy strategy to induce sustained proinsulin, the insulin precursor, production restored retinal insulin receptor signaling, by increasing S6 phosphorylation, without peripheral metabolic consequences. Moreover, proinsulin preserved photoreceptor synaptic connectivity and prolonged visual function in electroretinogram and optomotor tests. These findings point to a disease-modifying role of insulin receptor and support the therapeutic potential of proinsulin in retinitis pigmentosa. |
format | Online Article Text |
id | pubmed-9021205 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90212052022-04-28 Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa Sánchez-Cruz, Alonso Hernández-Pinto, Alberto Lillo, Concepción Isiegas, Carolina Marchena, Miguel Lizasoain, Ignacio Bosch, Fátima de la Villa, Pedro Hernández-Sánchez, Catalina de la Rosa, Enrique J. Cell Death Dis Article Synaptic loss, neuronal death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa (RP), the leading cause of inherited blindness, is a group of retinal dystrophies characterized by photoreceptor dysfunction and death. The insulin receptor, a key controller of metabolism, also regulates neuronal survival and synaptic formation, maintenance, and activity. Indeed, deficient insulin receptor signaling has been implicated in several brain neurodegenerative pathologies. We present evidence linking impaired insulin receptor signaling with RP. We describe a selective decrease in the levels of the insulin receptor and its downstream effector phospho-S6 in retinal horizontal cell terminals in the rd10 mouse model of RP, as well as aberrant synapses between rod photoreceptors and the postsynaptic terminals of horizontal and bipolar cells. A gene therapy strategy to induce sustained proinsulin, the insulin precursor, production restored retinal insulin receptor signaling, by increasing S6 phosphorylation, without peripheral metabolic consequences. Moreover, proinsulin preserved photoreceptor synaptic connectivity and prolonged visual function in electroretinogram and optomotor tests. These findings point to a disease-modifying role of insulin receptor and support the therapeutic potential of proinsulin in retinitis pigmentosa. Nature Publishing Group UK 2022-04-20 /pmc/articles/PMC9021205/ /pubmed/35444190 http://dx.doi.org/10.1038/s41419-022-04839-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Sánchez-Cruz, Alonso Hernández-Pinto, Alberto Lillo, Concepción Isiegas, Carolina Marchena, Miguel Lizasoain, Ignacio Bosch, Fátima de la Villa, Pedro Hernández-Sánchez, Catalina de la Rosa, Enrique J. Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa |
title | Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa |
title_full | Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa |
title_fullStr | Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa |
title_full_unstemmed | Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa |
title_short | Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa |
title_sort | insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021205/ https://www.ncbi.nlm.nih.gov/pubmed/35444190 http://dx.doi.org/10.1038/s41419-022-04839-0 |
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